The characterization and quantification of individual proteins or complex biological molecules is extremely important in fields as distant as medicine, forensics and the military. For example in medicine the presence and concentration of given proteins can be used for disease or pre-disease diagnoses. In the military given proteins can be used to signal the presence or absence of given pathogens in the environment which is extremely important for example in potential germ warfare situations.
The detection of individual proteins or molecules in biological samples is currently complex and generally requires sophisticated and bulky equipment.
Several technologies have recently been disclosed to characterize given biological molecules. In particular success has been achieved in high density DNA chips build by Affymetrix as originally described in PCT International Publication No. WO 90/15070.
U.S. Pat. No. 5,624,537, entitled "BIOSENSOR AND INTERFACE MEMBRANE", describes a protein-receiving matrix and a single electrode.
U.S. Pat. No. 5,395,587, entitled "SURFACE PLASMON RESONANCE DETECTOR HAVING COLLECTOR FOR ELUTED LIGATE", describes a system to measure immobilized ligands using a plasmon resonance detector.
U.S. Pat. No. 5,607,567 entitled "PROTAMINE-RESPONSIVE POLYMERIC MEMBRANE ELECTRODE", describes a membrane electrode.
U.S. Pat. No. 5,328,847 entitled "THIN MEMBRANE SENSOR WITH BIOCHEMICAL SWITCH", describes a biosensor with a specific recognition biomolecule.
U.S. Pat. No. 4,777,019 entitled "BIOSENSOR", describes a biosensor for biological monomers.
U.S. Pat. No. 5,532,128, entitled "MULTI-SITE DETECTION APPARATUS", describes test wells combined with electrodes to detect given biological molecules.
U.S. Pat. No. 4,983,510 entitled "ENZYMES IMMOBILIZED ON LATEX POLYMER PARTICLES FOR USE WITH AN AMINO ACID ELECTROSENSOR", describes an electrosensor with a latex polymer trap.
U.S. Pat. No. 5,384,028 entitled "BIOSENSOR WITH A DATA MEMORY", describes a membrane biosensor with a memory module.
U.S. Pat. No. 5,567,301 entitled "ANTIBODY COVALENTLY BOUND FILM IMMUNOBIOSENSOR", describes an antibody biosensor.
U.S. Pat. No. 5,310,469 entitled "BIOSENSOR WITH A MEMBRANE CONTAINING BIOLOGICALLY ACTIVE MATERIAL", describe s a membrane biosensor.
U.S. Pat. No. 5,019,238 entitled "MEANS FOR QUANTITATIVE DETERMINATION OF ANALYTE IN LIQUIDS", describes a means to sequentially test the ionic concentration of fluids.
U.S. Pat. No. 4,981,572 entitled "ELECTRODE UNIT AND PACKAGE FOR A BLOOD ANALYZER", describes an electrode and apparatus to analyze blood.
U.S. Pat. No. 4,452,682 entitled "APPARATUS FOR MEASURING CLINICAL EMERGENCY CHECK ITEMS OF BLOOD", describes an apparatus to measure multiple elements in blood.
U.S. Pat. No. 4,568,444 entitled "CHEMICAL SUBSTANCE MEASURING APPARATUS", describes an electrode to quantify chemical substances in a solution.
U.S. Pat. No. 5,281,539 entitled "IMMUNOASSAY DEVICE FOR CONTINUOUS MONITORING", describes a two step immunoassay device.
U.S. Pat. No. 5,192,507 entitled "RECEPTOR-BASED BIOSENSORS", describes a biosensor based on a polymeric film to detect opiates.
U.S. Pat. No. 5,156,810 entitled "BIOSENSORS EMPLOYING ELECTRICAL, OPTICAL AND MECHANICAL SIGNALS", describes a thin layer biosensor.
U.S. Pat. No. 5,494,831 entitled "ELECTROCHEMICAL IMMUNOSENSOR SYSTEM AND METHODS", describes an immunologic biosensor.
U.S. Pat. No. 5,332,479 entitled "BIOSENSOR AND METHOD OF QUANTITATIVE ANALYSIS USING THE SAME", describes an electrode based sensor with a biologically active receptor.
U.S. Pat. No. 5,582,697 entitled "BIOSENSOR, AND A METHOD AND A DEVICE FOR QUANTIFYING A SUBSTRATE IN A SAMPLE LIQUID USING THE SAME", describes a biosensor based on the measure of reduction between a substrate and an oxidoreductase.
U.S. Pat. No. 4,908,112 entitled "SILICON SEMICONDUCTOR WAFER FOR ANALYZING MICRONIC BIOLOGICAL SAMPLES", describes a micro capillary separation device with detector capabilities.
U.S. Pat. No. 5,409,583 entitled "METHOD FOR MEASURING CONCENTRATIONS OF SUBSTRATES IN A SAMPLE LIQUID BY USING A BIOSENSOR", describes a two step biosensor.
U.S. Statutory Invention H201 entitled "BIOSENSORS FROM MEMBRANE PROTEINS RECONSTITUTED IN POLYMERIZED LIPID BILAYERS", describes a method for incorporating and using cell membrane proteins in biosensors.
The above described technologies are generally used for the detection of a single type or a few different types of molecules. None of these technologies are particularly adapted to allow a very large number of different types of proteins, protein variants or other biological molecules to be detected and quantified simultaneously on a single chip. Furthermore none of the prior art provides a suitable technology to directly build protein-specific electronic receptors on a chip without the use of any biological binding agents, synthetic probes or complex micro-structures such as test wells.
We disclose herein a novel, smaller, faster and more cost effective technique to detect, characterize and quantify individual proteins or other complex molecules on a chip. The technology described herein may also serve as a new method for DNA sequencing.